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WO1992021336A1 - Produits analogues aux tocopherols abaissant le taux de cholesterol - Google Patents

Produits analogues aux tocopherols abaissant le taux de cholesterol Download PDF

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Publication number
WO1992021336A1
WO1992021336A1 PCT/US1992/003738 US9203738W WO9221336A1 WO 1992021336 A1 WO1992021336 A1 WO 1992021336A1 US 9203738 W US9203738 W US 9203738W WO 9221336 A1 WO9221336 A1 WO 9221336A1
Authority
WO
WIPO (PCT)
Prior art keywords
medicine
dihydro
benzopyran
methyl
dimethyl
Prior art date
Application number
PCT/US1992/003738
Other languages
English (en)
Inventor
Keith M. Robinson
Eric W. Heineke
Original Assignee
Merrell Dow Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merrell Dow Pharmaceuticals Inc. filed Critical Merrell Dow Pharmaceuticals Inc.
Priority to AU19935/92A priority Critical patent/AU665353B2/en
Priority to EP92912113A priority patent/EP0586518B1/fr
Priority to JP05500412A priority patent/JP3072912B2/ja
Priority to KR1019930703736A priority patent/KR100196973B1/ko
Priority to CA002102812A priority patent/CA2102812C/fr
Priority to DE69218196T priority patent/DE69218196T2/de
Publication of WO1992021336A1 publication Critical patent/WO1992021336A1/fr
Priority to NO934397A priority patent/NO304874B1/no
Priority to GR970401063T priority patent/GR3023646T3/el

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • This invention relates to alkylamino alkylene deriva ⁇ tives of certain 2H-l-benzopyrans useful as cholesterol lowering agents and to their end-use application as thera ⁇ Promotionic agents.
  • R ⁇ and R 2 each individually is a C 1 _ 6 lower alkyl
  • R 5 is H or C- ⁇ g alkyl
  • R 5 is H or -C(0)R, R being H or C- ⁇ g alkyl,
  • R- is H or C 1 _ 6 alkyl
  • R ⁇ is H or C 1 _ 6 alkyl and n is an integer of 1 to 6.
  • the moiety (CH 2 ) n of Formula I wherein n is an integer of one to six represents a C 1-6 straight or branched-chain alkylene including such preferred species as methylene, ethylene, propylene, t-butylene f n-butylene, n-hexylene and isopropylene.
  • C _ 6 alkyl include the straight and branched-chain radicals having up to six carbon atoms with methyl, ethyl, propyl, n-butyl, t-butyl, pentyl and hexyl being representative.
  • -C(0)R with R being H or C- ⁇ g alkyl, embraces for yl and the straight and branched-chain alkylcarbonyl moieties having up to ten carbon atoms including methylcarbonyl, ethylcar- bonyl, propylcarbonyl, t-butylcarbonyl and n-hexylcarbonyl as preferred representatives.
  • aryl preferably is phenyl or alkylated phenyl, and aralkyl is benzyl or phenylethyl, and their alkylated derivatives.
  • the pharmaceutically acceptable salts include those acid addition salts derived by reaction with such acids as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids and such organic carboxylic acids as acetic, propionic, glycolic, maleic, tartaric, citric, salicylic, 2-acetyloxybenzoic acids or organic sulfonic acids such as methanesulfonic 4-toluenesulfonic as naphthalenesulfonic acids.
  • the compounds of Formula I may be prepared by standard chemical processes and techniques analogously known in the art.
  • the preparation of the com ⁇ pounds of Formula I conveniently utilizes 3,4-dihydro-2,5,- 7,8-tetramethyl-2i?-l-benzopyran-2-ols as starting materials which, for the most part, are known compounds.
  • any specific starting material is not known then such compounds may readily be prepared using the standard procedures analogously known in the art as well as by applying such processes as would be reasonably expected to produce the desired starting materials.
  • the preparation of the 3,4-dihydro-2,5,7,8-tetramethyl- 2H-l-benzopyran-2-ols and their conversion to the final products of Formula I is depicted in the following reaction scheme.
  • R l R 2 , R 5 , R 6 , R 7 , R 8 and n are as previously defined, and X is an activating moiety, such as a halide (preferably Cl, Br or I) or 0-S(0) 2 R 4 , R 4 being H, C ⁇ _ 6 alkyl, aryl or aralkyl [preferably a tosylate CH 2 C 6 H 5 - S(0) 2 -0], and R 6 ' is -C(0)R with R being H or C ⁇ _ 9 alkyl.
  • a halide preferably Cl, Br or I
  • 0 0
  • R 6 ' is -C(0)R with R being H or C ⁇ _ 9 alkyl.
  • Introduction of the hydroxyalkyl moiety at the 2- position of the compounds of Formula (IV) can be effected by Wittig or Horner type reactions, preferably by reaction of the compounds of Formula (IV) with a trimethylphosphono- ester (e.g., trimethylphosphonoacetate) to yield the esters of Formula (V) which are hydrolyzed, and then reduced (preferably with lithium aluminum hydride) to yield the alcohols of Formula (VI).
  • These alcohols may also be formed directly by an acid catalyzed condensation of the hydroquinones (II) with the appropriate vinyl diols of Formulae (IX )and (X). 0H (CH 2 ) 2 OH
  • IX X n being as defined above.
  • the alcohols of Formula (VI) are first activated by converting the 2-position hydroxyalkyl moieties to either their halides or tosylates (preferably X is a halide or a p-toluenesulfonyl radical) or other equivalently functioning activating moiety, according to standard conditions such as for example reaction of the alcohols with bromotriphenylphosphonium bromide (0 3 PBr + Br ⁇ ) obtained by reaction of triphenylphosphine with bromine in dichloromethane, or by reacting the alcohols with the appropriate sulfonyl halide (e.g., p-toluenesulfonyl chloride) in the presence of a base according to standard conditions well known in the art.
  • sulfonyl halide e.g., p-toluenesulfonyl chloride
  • the resulting activated compounds (VII) may be converted to the desired dialkyl- amino derivatives either before (most preferred) or after acylation of the 6-OH moiety.
  • Standard procedures such as the reaction of the activated moiety with the appropriate dialkylamine, i.e., contacting equimolar quantities of the reactants at temperatures of about 30°C to 90°C with stirring in an inert solvent, preferably dimethylforma ide, may be used to obtain the dialkylamino derivative, and standard acylation procedures such as reaction of the 6-OH moiety with an acyl halide, acid anhydride or carboxylic acid produce the desired alkylcarbonyloxy moiety at the 6- position.
  • the compounds may occur as either the R- or the S-enantiomers, or mixtures thereof.
  • the preparation of the individual enantiomeric form may be effected by resolving the acids of Formula (V) by standard and conventional means such as, for example, via the use of diastereomeric salts with optically active amines, or alternatively, by resolving the alcohols (VII) as esters with optically active acids, e.g., L-2,4-MeClC 6 H 3 CHMeCOOH (Me representing methyl) .
  • optically active acids e.g., L-2,4-MeClC 6 H 3 CHMeCOOH (Me representing methyl
  • optically active enantiomers are obtained by substituting racemic 3,4-dihydro-6-hydroxy-2,5,7,8-tetra- methyl-2H-l-benzopyran-3-ethanol with enantiomer R- (CAS 94425-68-0) or S- (CAS-94425-67-9) and by following the procedures of this example for each individual isomer.
  • Vitamin E i.e., ⁇ -tocopherol, a well known compound of the formula
  • the compounds of this invention also possess a related or similar 3 , 4-dihydroxy-2 , 5 , 7 , 8-tetraalkyl-2H-l-benzopy- ran-2-yl moiety, but the 2-position lipophylic moiety of the ⁇ -tocopherol molecule, which is thought to be respon- sible for its ubiquitous incorporation into biomembranes, is replaced with a hydrophylic moiety to impart a greater affinity for cardiac tissue.
  • the compounds of this invention are also useful as pharmacologic antioxidants and free radical scavengers and, in particular, as scavengers of superoxide anion radical 0 2 " .
  • Tissues subjected to transient ischemia or reperfusion in various disease states, or by their medical treatment are those of heart, lung, kidney, pancreas and brain.
  • a free radical scavenger such as the compounds of this invention.
  • surgical interventions such as percutaneous transluminal coronary angioplasty, where a dilating balloon is used to increase the luminal diameter in severely occluded atherosclerotic vessels, coronary by ⁇ pass operations, and organ transplant surgery create conditions where reperfusion damage due to oxygen-derived radicals takes place and can be reduced by scavengers.
  • Transient ischemia is one of the causative factors that lead to angina pectoris, and thus the compounds of this invention are also useful as antianginal agents.
  • the process of inflammation is also known to involve the release of superoxide radicals from phagocytic cells which cause some of the symptoms of rheumatoid arthritis and a free radical scavenger, such as the compounds of this invention, is also useful in the treatment of this disease.
  • the compounds may also be useful in the treatment of cancers, diabetes, and of aging since oxygen-derived free radicals have been identified among causative factors. For reviews, see B. Halliwell and C. Gutteridge, Biochem. J., 119, 1-14 (1984); TINS 1985, 22-6; A.L. Drash, et al., Am. J. Cardiol., 62., 27B-30B (1988).
  • the subject compounds also exhibit plasma cholesterol- lowering activity as demonstrated by the following test data.
  • CD-I mice from the Charles River Laboratory were fed a diet (Purina Rodent Chow 5001) with or without 3,4-dihydro- 2-(2-dimethylaminoethyl)-2,5,7,8-tet ramehtyl-2H-l-benzo- pyran-6-ol for either one or two weeks. Blood samples were collected form the tail vein at 1 week. Two week blood samples were collected from decapitated mice.
  • CD-I mice from Charles River were fed a diet (Purina Rodent Chow 5001) with or without Compound A for 1 week. Blood samples were collected from the tail vein at 2, 4, and 7 days on study. Animals were then placed on control diet and tested again after 2 and 4 days (days 9 and 11 on study) after being removed from the drug. One percent of Compound A lowered plasma cholesterol 74% after 4 days of treatment. The effect was completely reversible 4 days after removal from the drug.
  • the db/db mouse is an animal model of type II diabetes. Blood samples were collected from the tail vein at 10, 20, 30, and 40 days on study.
  • Compound A lowered plasma cholesterol in a dose-dependent fashion and was effective at the lowest dose used (0.1% of Compound A).
  • the compounds are administered intravenously particularly under crisis situations wherein it is essential that the therapeutic agent be gotten to its site of action as quickly as possible, such as in those emergency conditions caused by coronary infarction, stroke and surgical interventions, conditions which can cause severe reperfusion damage.
  • the compounds of this invention can be utilized both prophylactically and therapeutically.
  • the amount of active ingredient for therapeutic administration can vary over a wide range and is dependent upon such factors as the species of mammal to be treated, its age, health, sex, weight, nature and the severity of the condition being treated. Generally, a therapeutically effective amount of the active ingredient to be administered will range from about 0.1 mg/kg to 50 g/kg of body weight per day. For prophylactic administration, corresponding lower doses can be utilized.
  • the compounds of this invention also can be orally administered, preferably using more active ingredient per day than when parenterally administered, preferably taking divided doses 3 to 4 times per day.
  • enteral administration in post "crisis" situations, particularly after release from hospitalized conditions.
  • the compounds can be used in standard dosage unit forms such as tablets, capsules, dragees, lozenges, elixirs, emulsions, suspen ⁇ sions, and in cases wherein topical application is pre ⁇ ferred by suppository or sublingual administration. Tablets and capsules containing from 100 to 400 g of active ingredient are preferred modes of enteral adminis ⁇ tration.
  • the preferred method of administration is by depot injection directly to the situs of the inflammation area with follow- up enteral means of administration.
  • the active ingredient is generally blended with conventional pharmaceutical carriers or excipients such as gelatin, various starches, lactose, calcium phosphate or powdered sugar.
  • pharmaceutical carrier as used herein also includes lubricants employed to improve the flow of tablet granulations and which prevent adhesion of tablet material to the surfaces of tablet dies and punches. Suitable lubricants include, for example, talc stearic acid, calcium stearate, magnesium stearate and zinc stearate.
  • disintegrating agents added to assist the breakup and dissolution of tablets following adminis- tration, as well as coloring and/or flavoring agents to enhance the esthetic qualities of the tablets and make them more acceptable to the patient.
  • Suitable liquid excipients for the preparation of liquid dosage unit forms include water and alcohols such as ethanol, benzyl alcohol and the polyethylene glycols, either with or without the addition of a surfactant.
  • the preferred liquid excipients, particularly for injectable preparations include water, physiological and saline solutions, dextrose and glycol solutions such as an aqueous propylene glycol or polyethylene glycol solutions.
  • such compositions may contain a nonionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulations ranges from about 5 to 15% by weight.
  • the surfactant can be a single component having the above- identified HLB, or a mixture of two or more components having the desired HLB.
  • Illustrative of surfactants useful in parenteral formulations are the class of polyoxyethylene sorbitan fatty acid esters as, for example, sorbitan mono- oleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • various oils can be utilized as carriers or excipients.
  • oils are mineral oils, glyceride oils such as lard oil, cod liver oil, peanut oil, sesame oil, corn oil and soybean oil.
  • suspending agents may be added as well as agents to control the viscosity, as for example, magnesium aluminum silicate or carboxymethyl- cellulose.
  • agents to control the viscosity as for example, magnesium aluminum silicate or carboxymethyl- cellulose.
  • buffers, preservatives and emulsifying agents may also be added.
  • the preferred compounds of Formula I are those wherein R 5 , R 7 and R 8 are methyl; wherein R 6 is formyl, methyl carbonyl, t-butylcarbonyl, ethylcarbonyl, propylcarbonyl, pentylcarbonyl; wherein n is 2 (repre ⁇ senting an ethylene moiety), and R ⁇ and R 2 substituents attached to the nitrogen atom are methyl.
  • Preferred com- pounds are those as illustrated in the examples showing the preparation of the compounds of Formula I.
  • the 2-position methyl moiety may be removed or replaced with another lower alkyl (e.g., the 2-position methyl may be replaced with H, ethyl. propyl, butyl and the like).
  • Such so-modified compounds are also contemplated within the scope of this invention for the utilities herein alleged, and may be prepared by standard procedures obvious to those skilled in the art.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Cette invention concerne des alkylamino alkylènes derivés de certains 2H-1-benzopyrannes utiles en tant qu'agents abaissant le taux de cholestérol dans le plasma et leur utilisation finale en tant qu'agents thérapeutiques.
PCT/US1992/003738 1991-06-05 1992-05-06 Produits analogues aux tocopherols abaissant le taux de cholesterol WO1992021336A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU19935/92A AU665353B2 (en) 1991-06-05 1992-05-06 Cholesterol-lowering tocopherol analogs
EP92912113A EP0586518B1 (fr) 1991-06-05 1992-05-06 Produits analogues aux tocopherols abaissant le taux de cholesterol
JP05500412A JP3072912B2 (ja) 1991-06-05 1992-05-06 コレステロール低下トコフェロール類似体
KR1019930703736A KR100196973B1 (ko) 1991-06-05 1992-05-06 콜레스테롤 강하용 약제학적 조성물
CA002102812A CA2102812C (fr) 1991-06-05 1992-05-06 Analogues du tocopherol hypolipidemiants
DE69218196T DE69218196T2 (de) 1991-06-05 1992-05-06 Cholesterinsenkende tocopherolanaloga
NO934397A NO304874B1 (no) 1991-06-05 1993-12-03 Anvendelse av kolesterolnedsettende tokoferolanaloger
GR970401063T GR3023646T3 (en) 1991-06-05 1997-05-12 Cholesterol-lowering tocopherol analogs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US710,647 1991-06-05
US07/710,647 US5135945A (en) 1991-06-05 1991-06-05 Cholesterol-lowering tocopherol analogs

Publications (1)

Publication Number Publication Date
WO1992021336A1 true WO1992021336A1 (fr) 1992-12-10

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Application Number Title Priority Date Filing Date
PCT/US1992/003738 WO1992021336A1 (fr) 1991-06-05 1992-05-06 Produits analogues aux tocopherols abaissant le taux de cholesterol

Country Status (16)

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US (1) US5135945A (fr)
EP (1) EP0586518B1 (fr)
JP (1) JP3072912B2 (fr)
KR (1) KR100196973B1 (fr)
AT (1) ATE149830T1 (fr)
AU (1) AU665353B2 (fr)
CA (1) CA2102812C (fr)
DE (1) DE69218196T2 (fr)
DK (1) DK0586518T3 (fr)
ES (1) ES2101848T3 (fr)
GR (1) GR3023646T3 (fr)
HU (1) HUT65738A (fr)
IE (1) IE921811A1 (fr)
NO (1) NO304874B1 (fr)
NZ (1) NZ242982A (fr)
WO (1) WO1992021336A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3230699B2 (ja) 1991-10-02 2001-11-19 メレル ファ−マス−ティカルズ インコ−ポレイテッド 心臓保護トコフェロ−ル類似体

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2082004A1 (fr) * 1991-11-20 1993-05-21 David Laffan Pentaalkylchromanes substitutes
CA2319131A1 (fr) 1998-01-26 1999-07-29 Walter H. Moos Agents protegeant les mitochondries et utilises dans le traitement des maladies associees aux mitochondries
CA2345079C (fr) 1998-09-23 2011-06-21 Research Development Foundation Tocopherols, tocotrienols, autres derives de chromane et de chaines laterales et leurs utilisations
US6770672B1 (en) 1998-09-23 2004-08-03 Research Development Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
US6703384B2 (en) * 1998-09-23 2004-03-09 Research Development Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
CN1243000C (zh) * 2000-02-11 2006-02-22 研究发展基金会 生育酚、生育三烯酚、其它苯并二氢吡喃和侧链衍生物,及其用途
US6436406B1 (en) * 2000-06-15 2002-08-20 A. Glenn Braswell Compositions and methods for reducing or controlling blood cholesterol, lipoproteins, triglycerides and atherosclerosis
US20030236301A1 (en) * 2001-12-19 2003-12-25 Bob Sanders Liposomal delivery of vitamin E based compounds
AU2003226209B2 (en) * 2002-03-21 2008-10-23 Dana-Farber Cancer Institute, Inc. Inhibition of cell death responses induced by oxidative stress

Citations (3)

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US4603142A (en) * 1984-06-01 1986-07-29 Wisconsin Alumni Research Foundation Cholesterol lowering method of use
EP0369082A1 (fr) * 1988-11-14 1990-05-23 Merrell Dow Pharmaceuticals Inc. Analogues de tocophérol ayant des propriétés cardioprotectrices
EP0421419A2 (fr) * 1989-10-04 1991-04-10 Bristol-Myers Squibb Company TocotriÀ©nols pour le traitement de l'hypercholestérolémie, de l'hyperlipidémie et des troubles thromboemboliques

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US4321270A (en) * 1981-01-29 1982-03-23 E. R. Squibb & Sons, Inc. Substituted chromans
US4681890A (en) * 1984-10-30 1987-07-21 Kuraray Co., Ltd. 3,4-dihydrobenzopyran compounds and pharmaceutical composition containing the same
CA2002649C (fr) * 1988-11-14 2000-06-06 Margaret Petty Analogues de tocopherol cardioprotecteurs

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US4603142A (en) * 1984-06-01 1986-07-29 Wisconsin Alumni Research Foundation Cholesterol lowering method of use
EP0369082A1 (fr) * 1988-11-14 1990-05-23 Merrell Dow Pharmaceuticals Inc. Analogues de tocophérol ayant des propriétés cardioprotectrices
EP0421419A2 (fr) * 1989-10-04 1991-04-10 Bristol-Myers Squibb Company TocotriÀ©nols pour le traitement de l'hypercholestérolémie, de l'hyperlipidémie et des troubles thromboemboliques

Non-Patent Citations (1)

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Title
Int. J. Clin. Pharmacol., vol. 10, no. 2, 1974; O. Aigner et al.: "Die Wirkung von Tocopherolnikotinat auf die Serumlipide", pages 124-128, see the whole article *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3230699B2 (ja) 1991-10-02 2001-11-19 メレル ファ−マス−ティカルズ インコ−ポレイテッド 心臓保護トコフェロ−ル類似体

Also Published As

Publication number Publication date
GR3023646T3 (en) 1997-08-29
NZ242982A (en) 1997-03-24
ES2101848T3 (es) 1997-07-16
NO934397L (no) 1993-12-03
IE921811A1 (en) 1992-12-16
EP0586518A1 (fr) 1994-03-16
CA2102812C (fr) 2004-03-30
JPH06508134A (ja) 1994-09-14
NO934397D0 (no) 1993-12-03
NO304874B1 (no) 1999-03-01
US5135945A (en) 1992-08-04
JP3072912B2 (ja) 2000-08-07
DE69218196D1 (de) 1997-04-17
KR940701251A (ko) 1994-05-28
DE69218196T2 (de) 1997-07-17
AU1993592A (en) 1993-01-08
HUT65738A (en) 1994-07-28
KR100196973B1 (ko) 1999-06-15
CA2102812A1 (fr) 1992-12-06
AU665353B2 (en) 1996-01-04
EP0586518B1 (fr) 1997-03-12
ATE149830T1 (de) 1997-03-15
DK0586518T3 (da) 1997-04-01

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